Thiophene-2-carboxylic acid

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

Finally, certain 3-substituted compounds can be prepared by utilizing the - meta) directing powet (cf. Section IV,B) of some groups in the 2-position which afterward can be removed. 3-Nitrothiophene is prepared by nitration of 2-thiophenesulfonyl chloride and by removal of the sulfonic acid group of the 4-nitro-2-sulfonyl chloride formed with superheated steam. Another approach to 3-nitrothio-phene is to nitrate 2-cyanothiophene, separate the 4-nitro-2-cyano-thiophene from the 5-isomer, hydrolyze, and decarboxylate. A final method of preparation of 3-nitrothiophene is by simultaneous de-bromination and decarboxylation of 5-bromo-4-nitro-2-thiophene-carboxylic acid obtained through the nitration of methyl 5-bromo-2-thiophenecarboxylate. 

Chamical Nama 4-Methyl-3-[ [ 1 -oxo-2-(propylamino) propyl] amino]-2-thiophene carboxylic acid methyl ester... 

A thermophilic strain M. goodii X7B was reported to carry out desulfurization of BT and DBT [38], The growth of the strain on various sulfur substrates including DBT, BT, 4,6-dimethyl DBT, 5-methyl BT, 2-thiophene carboxylic acid and propylmercaptan was studied at 45°C and varying degree of growth was observed. A mechanism of sulfur removal was proposed for BT based on metabolites identified by GC-MS (Fig. 7 [125]). 

The reaction of butadiene with the sulfone of 3-benzo[6]thiophene-carboxylic acid under Diels-Alder conditions gives the adduct (32). Catalytic reduction over platinum oxide removes the 2,3-double bond. 

Metallation of dibenzothiophene 5-oxide with three equivalents of butyllithium followed by carbonation gave a mixture of 4-dibenzo-thiophene carboxylic acid (36 /o) and dibenzothiophene (10%). The reduction or even elimination of sulfoxide groups in the presence of... 

Polymers of thiophene carboxylic acids (9) undergo different chromatic transitions upon the addition of a variety of cations (McCullough et al. 1997). Although the acid form of the polymer was not water soluble, addition of various ammonium or metal... 

This synthetic fiexibility was put to use in the preparation of " C-labeled isotopomers of duloxetine (3) for further biological studies (Scheme 14.12). Labeled thiophene carboxylic acid 40 was readily converted to radioactive intermediate 43a, which was then converted to duloxetine-[3- " C] hydrochloride (3a ) via route A. In contrast, 43b was submitted to route B, utilizing labeled [l- C]-naphthalene, to provide duloxetine-[l-naphthalene- " C] hydrochloride (3b ). 

In a related report, ruthenium-catalyzed enantioselective hydrogenation of 3-keto esters was utilized to prepare the crucial alcohol intermediate 36 (Scheme 14.16). The required (3-keto ester 49 was readily prepared from commercial thiophene carboxylic acid 40. Hydrogenation of 49 then led to the desired (S)-alcohol 50 in quantitative yield and 90% enantiomeric excess, catalyzed by a chiral diphosphine-ruthenium complex generated in situ. Catalyst-substrate ratios used were as low as 1/20,000, rendering this approach amenable to industrial application. Alcohol 50 was then converted to known intermediate 36 in three steps and 60% overall yield. 

Pyrrole-2-carboxylic acid easily loses the carboxylic group thermally. Pyrrole-3-carboxylic acid and furan-2- and -3-carboxylic acids also readily decarboxylate on heating to about 200°C. Thiophene-carboxylic acids require higher temperatures or a copper-quinoline catalyst. In furans, 2-carboxylic acid groups are lost more readily than 3-carboxylic acid groups (Scheme 64). 

Thiophene- and benzo[6]thiophene-carboxylic acids undergo all the normal reactions of an aromatic carboxylic acid (63AHC(1)1, 70AHC(11)177). They can be converted to acid chlorides, amides and esters the esters can be used to make hydrazides. Benzo[6]thiophene-2-carboxylic acid chloride has been converted to the methyl ketone with dimethylcadmium and to the diazoketone with diazomethane. Bromodecarboxylation of the silver salts (Hunsdiecker reaction) has been used to prepare the dibromo compounds (340) and (341). 

A chloroacetylbenzo[6]thiophene is readily converted into the corresponding benzo[6]thiophene carboxylic acid by alkaline hydrolysis of its pyridinium salt.132 464... 

Esters, amides, and primary alcohols are obtained from benzo[6]-thiophene carboxylic acids by standard procedures.337 481,585 692 093,695 Acid chlorides undergo the Arndt-Eistert reaction,337,568,689 react with diethyl ethoxymagnesium malonate to give the corresponding methyl ketone,144 557 and are reduced to the aldehyde with 1 ithium tri-ferf-butoxy aluminohydride.33 7... 

Benzo[6]thiophene carboxylic acids have been decarboxylated byT heating them with oxalic acid,254 by heating the ester with IN NaOH in dioxane,441 by heating the barium salt with barium hydroxide in vacuo,162, by heating them in quinoline with copper chromite347, 352.353 or> preferably, with copper,109 185 189,298 315 343 344 351 412 422, 638 an(j py heating them alone in quinoline54 or pyridine.114... 

Carboxylic acids, acyl chlorides, and sulfonyl chlorides used for deri-vatization of 4-aminophenylalanine and >-4-am i n op h e ny I a I a n i n e are as follows 5-hydantoinacetic acid, / ran, v - 4 - co t i n i n ec a r b o xy I i c acid, isonicotinic acid, 3-pyridinepropionic acid, 4-hydroxyphenylacetic acid, 2-butynoic acid, 2-pyrazinecarboxylic acid, cyclopropanecarboxylic acid, 3-hydroxy-2-qui-noxaline carboxylic acid, 5-bromovaleric acid, propargyl chloroformate, 3,4-dimethoxybenzoyl chloride, 2-thiophenesulfonyl chloride, 3-thiophene-carboxylic acid, 2-thiophenecarboxylic acid, 2-methylbutyric acid, 2-thio-pheneacetyl chloride, benzoic acid, furylacrylic acid, 4-nitrophenyl acetic acid, 2,5-dimethoxyphenylacetic acid, p-toluenesulfonyl chloride, 4-(di-methylamino)phenylacetic acid, 3-indolepropionic acid, phenoxyacetic acid, 3-(dimethylamino)benzoic acid, cyclohexanecarboxylic acid, naphtha-lenesulfonyl chloride, 4-bromophenylacetic acid, 4-bromobenzoic acid, 2-phenoxybutyric acid, 3,4-dichlorophenylacetic acid, (l-naphthoxy)acetic acid. 

D-Arg H2N,COOH L. n nh2 NH Isonicotinic acid COOH 3-Thiophene carboxylic acid COOH Q... 

D-Arg h2N,co°h C n, nh2 NH Isonicotinic acid Cl COOH 2-Thiophene carboxylic acid C3 -cOOH... 

Ckbp" y) hiT nIj--cooh o Isonicotinic acid Cl - XOOH 3-Thiophene carboxylic acid COOH 0... 

HjO / pH - 5) are 2- and 3-mercaptopropionic-, furan-, and thiophene carboxylic acids, which amount to 40 to 80 % of the volatile Maillard products. The furan- and thiophene carboxylic acids are formed via 3-deoxyosone and the mercaptoacids via 1-deoxyosone (Figure 6). By dehydration, addition of H 0 (or by Strecker degradation of Cys) and reduction of the carbonyl group, furfuryl-mercaptan (the impact component of roasted coffee) results. 2-Hydroxymethyl-4-thiolanone, which may be formed by the same route, was identified for the first... 

Silver oxide, easily prepared from silver nitrate and sodium hydroxide, is probably the best reagent for the preparation of pure acids from aldehydes. An additional advantage is that it does not attack other easily oxidizable groups in the molecule. Typical examples are 3-thiophene-carboxylic acid (97%), palmitic acid (98%), and anthracene-9 carboxyIic acid (72%). Its use in the preparation ol olefinic acids from olefinic aldehydes is illustrated by the preparation of 2-methyI-2-pentenoic acid (60%). Organic peracids have also been used in the oxidation of aldehydes to carboxylic acids. ... 

Hinsberg synthesis of thiophene derivatives. Formation of thiophene carboxylic acids from a-diketones and dialkyl thiodiacetate. 

In 1967, two reactions that proceeded by the intramolecular cyclization mechanism and led to fluorinated benzo[Z>]thiophenes were carried out. The first is based on the reaction of the lithium salt of pentafluorothiophenol and diethyl acetylenedicarboxylic ether (67JCS(C)1225) (Scheme 148). Here the intermediate species is a carbanion. In the second process, the starting compound is a benzylidene rhodanine derivative, giving benzo[Z>]thiophene carboxylic acid 157 in alkaline media. This reaction occurs via the intermediate S-nucleophile (Scheme 149). 

The initial cyclization reaction in the previous synthesis is similar to that used in the formation of thienooxazinones (321) through the annulation of thiophene carboxylic acids (320) by thionyl chloride in the presence of DMF (Equation (34)) <80KGS45>. 

DEPC promoted the condensation reaction of thiophene carboxylic acid (37) and hydroxyethanol amine to give amide 38 in 63% yield.16 Amide 38 is a key intermediate used in the synthesis of thienopyrimidines. 

Homologues of thiophene occur in coal-tar they may be prepared by Fittig s synthesis and in other ways. Their properties are similar to those of the analogous benzene derivatives for example, thiotolene, methyl thiophene, is converted into thiophene carboxylic acid by oxidizing agents —... 

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

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